In this application we propose the development of small molecule inhibitors of the HIV Vif protein.[unreadable] While Vif has been recognized as an important gene for viral infectivity, the cellular mechanism[unreadable] responsible for this effect has only recently been elucidated. Vif functions to inactivate the cellular[unreadable] defense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering it[unreadable] noninfectious. Our previous work in vaccine development has demonstrated the crucial in vivo[unreadable] significance of Vif to viral replication in the rhesus macaque and supports the relevance of this drug[unreadable] target. The University of Massachusetts Medical School (UMMS) established a high throughput drug[unreadable] screening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of this[unreadable] venture, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitor[unreadable] screen and a number of lead compounds have been identified that have the potential to target peripheral[unreadable] and CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the further[unreadable] development of these Vif inhibiting agents. The application brings together a collaborative team with[unreadable] diverse expertise in medicinal chemistry, molecular virology, and in vivo systems to examine the clinical[unreadable] potential of such inhibitors.[unreadable] Our objective is to utilize pharmacokinetic and efficacy studies in rodent species in a lead[unreadable] optimization approach reserving proof-of-principal studies in nonhuman primates to the most promising[unreadable] drug candidates. Long term efficacy studies will allow us to examine the effect of Vif inhibitors on plasma[unreadable] viral load and markers of immunodeficiency as well as to evaluate the effect of drug treatment on SIV[unreadable] encephalitis, a lentiviral specific disease process. To accomplish these goals we propose the following[unreadable] specific aims:[unreadable] Specific aim 1: To define the pharmacokinetic and safety profile of novel Vif inhibitors in rodents[unreadable] and rhesus macaques.[unreadable] Specific aim 2: To examine the short term in vivo effect of Vif inhibitors on viral replication and[unreadable] cellular reservoirs in rodent and rhesus macaque models of HIV infection.[unreadable] Specific aim 3: To examine the efficacy of Vif inhibitors on biomarkers of CNS inflammation and[unreadable] morphologic evidence of CNS pathology in an SIV-macaque model of neuroAIDS.